4&#39;-phenoxyalkanesulfonanilides



United States Patent O 3,531,522 4'-PHENOXYALKANESULFONAN]LIDES Norman A. Nelson, Charlestown Township, Kalamazoo County, and Gary E. Vanden Berg, Texas Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed July 18, 1967, Ser. No. 654,064 Int. Cl. A01n 9/16; C07c 143/74 US. Cl. 260-556 4 Claims ABSTRACT OF THE DISCLOSURE Disclosed are lipid-normalizing 4-phenoxyalkanesulfonanilides which are derived from p-phenoxyanilines.

BACKGROUND OF THE INVENTION In is known that relatively high serum cholesterol and triglyceride levels are injurious to arterial tissue, and that such injuries may be one of the causes of coronary heart disease and atherosclerosis. It has now been found that the serum lipid level in a mammal, and in particular the cholesterol and the triglyceride levels, can be lowered by administering to the mammal an effective amount of a compound of the present invention.

SUMMARY OF THE INVENTION The compounds of this invention are 4'-phenoxyalkanesulfonanilides which can be represented by the formula wherein X can be halo, alkyl containing from 1 to 4 carbon atoms, inclusive, or alkoxy containing from 1 to 4 carbon atoms, inclusive; Y can be halo; R can be hydrogen, alkyl containing from 1 to 4 carbon atoms, inclusive, 3-piperidinopropyl, 2-piperidinoethyl, 3-(l-pyrrolidinyl)propyl, 2-(1-pyrrolidinyl)ethyl, 3-morpholinopropyl, 2-morpholinoethyl and dialkylaminoalkyl of the formula R8 --(CH2)kN where R and R can be alike or difierent and are alkyl containing from 1 to 4 carbon atoms, inclusive; and R can be alkyl containing from 1 to 6 carbon atoms, inclusive. The subscript k is an integer having a value of 2 or 3, and m and n are integers having a value of zero to 3, inclusive, and of zero to 2, inclusive, respectively. The foregoing compounds are useful as hypocholesterolemic and hypotriglyceridemic agents.

DETAILED DESCRIPTION OF THE INVENTION The instant compounds can be prepared by reacting a phenoxyaniline of the type O- NH Q Q l.

Xm Yn where X, Y, m and n have the same meaning as above and R is hydrogen or alkyl containing from 1 to 4 carbon atoms, inclusive, with an alkanesulfonyl halide represented by the formula (HI) HalogenSO -R where R has the same meaning as above, and Halogen preferably is chlorine or bromine.

3,531,522 Patented Sept. 29, 1970 In Formulas I and II illustrative halo radicals are fluoro, chloro, bromo, and iodo.

Illustrative of the alkyl radicals contemplated herein are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.- butyl, tert.-butyl, the pentyls, and the hexyls.

Illustrative alkoxy radicals are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, and tert.-butoxy.

The phenoxyanilines represented by Formula II are a known group of compounds, some of which are commercially available. Illustrative phenoxyanilines (II) are p- (p-chlorophenoxy aniline,

po-chlorophenoxy) aniline,

3 -chloro-4-phenoxyaniline,

4- p-chlorophenoxy) -3 ,5 -diiodoaniline, p- 2,4-dichlorophenoxy) aniline,

p- 2,5 -dichlorophenoxy) aniline,

p- (2,4-dibromophenoxy) aniline,

3,5 -diiodo-4-phenoxyaniline,

p- (p-bromophenoxy) aniline,

p- (p-iodophenoxy aniline,

p- (o-iodophenoxy) aniline, 3-iodo-4-phenoxyaniline,

pm-bromophenoxy) aniline,

p- 2,4,5 -trichlorophenoxy) aniline,

p- 2,4,6 -trichlorophenoxy) aniline,

p- (p-tert.-butylphenoxy) aniline, N-methyl-p-phenoxyaniline,

p- (p-tolyloxy) aniline,

p- 3,4-xylyloxy) aniline,

p- (p-methoxyphenoxy) aniline,

p- (m-methoxyphenoxy) aniline,

p- 3 ,5 -dimethoxyphenoxy) aniline,

p- (6-b romo-2,4-Xyly1oxy) aniline,

3 ,5 -diiodo-4- p-methoxyphenoxy) aniline, p (2,6-dimethoxyphenoxy) -N-isopropylaniline, N-sec.-butyl-pp-methoxyphenoxy) aniline, p-phenoxyaniline, and the like.

The alkanesulfonyl halides of Formula III are also a known class of compounds, and some are commercially available. Methods of preparation can be found in I. Am. Chem. Soc. 58, 1348 (1936); J. Am. Chem. Soc. 59, 1837, 2439 (1937); and J. Am. Chem. Soc. 60, 1486 (1938).

Illustrative alkanesulfonyl halides (III) are methanesulfonyl chloride, ethanesulfonyl chloride, butanesulfonyl chloride, propanesulfonyl chloride, l-methylethanesulfonyl chloride, sec.-butanesulfonyl chloride, isobutanesulfonyl chloride, pentanesulfonyl chloride, hexanesulfonyl chloride, etc.

The reaction between a phenoxyaniline (II) and an alkanesulfonyl halide (III) can be carried out by admixing one or more equivalents of the alkanesulfonyl halide with the phenoxy-aniline in a suitable reaction medium which is also an acid acceptor for the hydrogen halide formed during the reaction, such as pyridine, the alkylsubstituted pyridines, N,N-dimethyl-aniline, the tertiary alkylamines such as triethylamine, trimethylamine, etc., with or without inert cosolvents typified by methylene chloride, diethyl ether, benzene, tetrahydrofuran, or the like. The reaction temperature can range from about 0 C. to about 60 C. Room temperature is preferred, however.

The reaction product from the foregoing reaction is the desired 4-phenoxyalkanesulfonanilide (I) in which R is hydrogen or alkyl. The reaction product can be isolated from the reaction mixture in conventional manner, e.g., by filtration or extraction into a water-immiscible solvent, followed by washing and drying of the recovered product. If necessary, the product can be purified further by crystallization or by high vacuum distillation.

A 4-phenoxyalkanesulfonilide (I) where R is hydrogen can be alkylated by treatment, in an inert organic solvent such as benzene, tetrahydrofuran, or dioxane, with an alkylating agent which can be an alkyl halide or a sec.-aminoalkyl halide. The alkylation takes place in the presencepf a base, for example, an alkali metal alkoxide such as potassium tert.-butoxide, or an alkali metal hydride such as sodium hydride or potassium hydride. Reaction temperature for the alkylation reaction can range from about C. to about 100 C. When the alkylating agent is a primary alkyl iodide, room temperature is the preferred reaction temperature; however, for alkyl chlorides a temperature from about 50 C. to about 100 C. is preferred. When sec.-aminoalkyl halides in the form of a hydrohalide salt are employed as the alkylating agent, sufiicient base is added to the reaction mixture to liberate the free sec.-aminoalkyl halide and to form the sulfonanilide alkali metal salt.

Illustrative alkyl halides which can be used as alkylating agents are methyl iodide, ethyl iodide, propyl iodide, butyl iodide, methtyl bromide, ethyl chloride, propyl bromide, butyl chloride, sec.-butyl bromide, and the like.

Illustrative sec.-aminoalkyl halides suitable as alkylating agents are N,N-diethyl-2-chloroethylamine, N,N- dibutyl-2-chloro-ethylamine, N,N diethyl-3-chloropropylamine hydrochloride, N-methyl-N-propyl-3-bromopropylamine hydrochloride, N ethyl N-butyl-2-bromoethylamine, N-(Z-chloroethyl)piperidine, N-(3-chloropropyl) piperidine, N-(2-chloroethyl)pyrrolidine, N-(S-chloropropyl)pyrrolidine, N-(2-chloroethyl)morpholine, N-(3- chloropropyl)morpholine, and the like.

The compounds of the present invention where R is sec.-aminoalkyl are amines which can eXist either in the nonprotonated or free-base form, or in the protonated or acid addition salt form, depending on the pH of the environment. Stable, pharmaceutically acceptable protonates can be formed on neutralization of the free-base form with suitable acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, and the like.

The compounds of this invention have lipid-normalizing activity and thus are useful as hypocholesterolemic agents and as hypotriglyceridemic agents in mammals.

For purposes of administration, the compounds of this invention can be combined with solid or liquid pharmaceutical carriers and formulated in the form of tablets, powder packets, or capsules, using starch or similar excipients. The instant compounds can also be dissolved or suspended in suitable solvents or vehicles for oral or parenteral administration. If desired, the present active ingredients can also be admixed with food.

The amount of the active ingredient that is to be administered depends on the age, weight, and condition of the recipient, and also on factors such as the frequency and route of administration.

The daily dose range can be from about 0.1 milligram per kilogram of body weight to about 50 milligrams per kilogram of body weight.

The present invention is further illustrated by the following examples.

EXAMPLE I Preparation of 4-phenoxymethanesulfonanilide p-Phenoxyaniline (about 37 grams) was dissolved in pyridine (about 100 milliliters). The resulting solution was chilled to about 5 C. and methanesulfonyl chloride (about 15 milliliters) was added thereto.

The resulting admixture was stirred at about room temperature for about 4 hours, then diluted with water and ice. A precipitate was observed to form and was recovered by filtration. Upon recrystallization from methanol, about 35 grams of a product melting at 125 C. to 126 C., and about 9 grams of the same product melting at 124 C.

4- to 126 C. was obtained. An analytical sample melting at 126.5 C. to 127.5 C. was obtained after two additional recrystallizations, using charcoal once. The product was identified as 4'-phenoxymethanesulfonanilide, obtained in about 83 percent yield.

Analysis.Calcd for C H NO S (percent): C, 59.30; H, 4.98; S, 12.18. Found (percent): C, 59.22; H, 4.76; S, 12.09.

In a manner similar to Example I, but using ethanesulfonyl chloride as one of the reactants, the corresponding 4-phenoxyethanesulfonanilide can be prepared;

Using propanesulfonyl chloride the corresponding 4'- phenoxypropanesulfonanilide can be prepared;

Using butanesulfonyl bromide the corresponding 4- phenoxybutanesulfonanilide can be prepared;

Using pentanesulfonyl chloride the corresponding 4'- phenoxypentanesulfonanilide can be prepared;

Using hexanesulfonyl chloride the corresponding 4- phenoxyhexanesulfonanilide can be prepared; etc.

Similarly, reacting p-(p-chlorophenoxy)aniline with; methanesulfonyl chloride the corresponding 4'-(4-chlorophenoxy)methanesulfonanilide is produced;

Reacting 3-chloro-4-phenoxyaniline with ethanesulfonyl chloride the corresponding 3-chloro-4-phenoxyethanesulfonanilide is produced;

Reacting 4-(p-chlorophenoxy)-3,5-diiodoaniline with propanesulfonyl chloride the corresponding 4'-(4-chlorophenoxy)-3,5-diiodopropanesulfonanilide is produced;

Reacting p (2,4,5 trichlorophenoxy)aniline with butanesulfonyl chloride the corresponding 4-(2,4,5-trichlorophenoxy)-butanesulfonanilide is produced;

Reacting p-(p-tert.-butylphenoxy)aniline with methanesulfonyl chloride the corresponding 4'-(4-tert.-butylphenoxy)-methanesulfonanilide is produced;

Reacting N-methyl-p-phenoxyaniline with methanesulfonyl chloride the corresponding N-methyl-4'-phenoxymethanesulfonanilide is produced;

Reacting N butyl 4-(2,4,6-trimethylphenoxy)aniline with ethanesulfonyl chloride the corresponding N-butyl- 4 (2,4,6 trimethylphenoxy)ethanesulfonanilide is produced;

Reacting N ethyl 4-(2,4,6-trimethylphenoxy)-3,5-diiodoaniline with propanesulfonyl chloride the corresponding N ethyl 4'-(2,4,6-trimethylphenoxy)-3',5'-diiodopropanesulfonanilide is produced;

Reacting 3,5-diiodo-4-(2-methoxyphenoxy)aniline with butanesulfonyl chloride the corresponding 3,5-diiodo- 4-(2-methoxyphenoxy)butanesulfonanilide is produced;

Reacting 3,5-dibromo-4 (3-butoxyphenoxy)aniline with methanesulfonyl chloride the corresponding 3,5 dibromo-4'-(3 butoxyphenoxy)methanesulfonanilide is produced, etc.

EXAMPLE II Preparation of N-methyl-4'-phen0xymethanesulfonanilide 4'-phenoxymethanesulfonanilide (about 10 grams) was dissolved in dry tetrahydrofuran (about milliliters). To the resulting solution was added potassium cert.- butoxide (about 4.5 grams) and methyl iodide (about 15 milliliters), and the produced admixture was stirred for about 4 hours, and then the tetrahydrofuran was removed by evaporation in vacuo. The obtained residue was dissolved in methylene chloride-water, and the produced organic layer was separated. The organic layer was washed well with dilute aqueous sodium hydroxide and Water, and then dried over magnesium sulfate. The dried organic layer was evaporated in vacuo and the produced solids recrystallized from ethyl acetate-mixed hexanes. About 7.7 grams of crystals melting at 112 C. to 113 C. was obtained. The crystals were identified as N-methyl-4'-phenoxymethanesulfonanilide, obtained in about 73 percent yield.

Analysis.-Calcd for C H NO S (percent): C, 60.63; H, 5.45; N, 5.05; S, 11.56. Found (percent): C, 60.56; H, 5.68; N, 5.17; S, 11.45.

EXAMPLE III Preparation of N-[Z-(diethylamino)ethyl]-4'- phenoxymethanesulfonanilide 4'-phenoxymethanesulfonanilide (about 16.75 grams), potassium tert.-butoxide (about 23.5 grams), N,N-diethyl 2-chloroethy1amine hydrochloride (about 22 grams), and dry tetrahydrofuran (about 200 milliliters) were admixed, stirred at about room temperature for about 4 hours, and then heated under reflux for about 30 hours.

Thereafter, the tetrahydrofuran Was removed by evaporation in vacuo, and the produced residue dissolved in methylene chloride-water. The obtained organic layer was separated and washed well with dilute aqueous sodium hydroxide and water, and then dried over sodium sulfate. The dried organic layer was evaporated in vacuo and the residue therefrom crystallized from ethyl alcoholwater.

About 10.6 grams of crystals melting at 71 C. to 75 C. and resolidifying and melting at 84 C. to 86 C. was obtained. One recrystallization from ethyl alcohol yielded crystals melting at 71 C. to 75 C. and resolidifying and melting at 86 C. to 87 C. The crystals were identified as N- [2-(diethylamino)ethyl]4 phenoxy methanesulfonanilide, obtained in about 46 percent yield.

Analysis.Calcd for C H N O S (percent): C, 62.95; H, 7.23; N, 7.73; S, 8.85. Found (percent): C, 62.92; H, 7.21; N, 7.73; S, 8.82.

In a manner similar to Example III but using N,N- dibutyl-2-chloroethylamine hydrochloride in lieu of N,N- diethyl-2-chloroethylamine hydrochloride the corresponding N-[Z-(dibutylamino)ethyl]-4' phenoxymethanesulfonanilide can be prepared;

Using N,Ndiethyl-3-chloropropylamine hydrochloride the corresponding N-[3-diethylamino)propyl] -4'-phenoxymethanesulfonanilide can be prepared.

Using N-methyl-N-propyl-3-chloropropylamine hydrochloride the corresponding N-[3-(N-methyl-N-propylamino)propyl]-4'-phenoxymethanesulfonanilide can be prepared;

Using N-(2-ch1oroethyl)piperidine the corresponding N-(2-piperidinoethyl)-4' phenoxyrnethanesulfonanilide can be prepared;

Using N-(3-chloropropyl)piperidine the corresponding N (3 piperidinopropyl) 4' phenoxymethanesulfonanilide can be prepared;

Using N-(2-chloroethyl)pyrrolidine the corresponding N-[2-(1-pyrrolidinyl)ethyl] 4 phenoxymethanesulfonanilide can be prepared;

Using N-(3-chloropropyl)pyrrolidine the corresponding N-[3-(1-pyrrolidinyl)propyl] 4'-phenoxymethanesulfonanilide can be prepared;

Using N-(2-chloroethyl)morpholine the corresponding N-(2-morpholinoethyl)-4' phenoxymethanesulfonanilide can be prepared;

formula o- 1 I-s 024a in n wherein X is a member of the grouping consisting of halo, alkyl containing from 1 to 4 carbon atoms, inclusive, and alkoxy containing from 1 to 4 carbon atoms, inclusive; Y is halo; R is a member of the grouping consisting of hydrogen, alkyl containing from 1 to 4 carbon atoms, inclusive, Z-piperidinoethyl, 3-piperidinopropyl, 2-( l-pyrrolidinyl ethyl, 3-( l-pyrrolidinyl) propyl, 2-morpholinoethyl, 3-morpholinopropyl, and dialkyl aminoalkyl of the formula RI --(CH2)k-N where R and R are alkyl containing from 1 to 4 carbon atoms, inclusive; R is alkyl containign from 1 to 6 carbon atoms, inclusive; m is an integer having a value of zero to 3, inclusive; n is an integer having a value of zero to 2, inclusive; and k is an integer having a value of 2 to 3, inclusive; and the corresponding pharmaceutically acceptable acid addition salts.

2. The 4-phenoxyalkanesulfonanilide in accordance with claim 1 wherein R is hydrogen, R is methyl, and m and n have a value of zero.

3. The 4'-phenoxyalkanesulfonanilide in accordance with claim 1 wherein R and R are methyl, and m and n have a value of zero.

4. The 4-phenoxyalkanesulfonanilide in accordance with claim 1 wherein R is dialkylaminoalkyl with R and R both ethyl and k has a value of 2, R is methyl, and mi and n have a value of zero.

References Cited UNITED STATES PATENTS 3,223,582 12/1965 Bindler et al. l6730 OTHER REFERENCES Smith, The Chemistry of Open Chain N-cpds. I (Benjamin, New York, 1965), p. 73.

HENRY R. JILES, Primary Examiner C. M. SHURKO, Assistant Examiner U.S. C1. X.R. 

